Several studies suggest that certain infections, including periodontal infections, predispose to atherosclerotic disease. INVEST has contributed significantly to this field. In INVEST period one, we have found that periodontal disease is cross-sectionally associated with carotid artery intima media thickness (IMT). We have further reported that bacteria presumptively causally related to clinical periodontal disease are related positively to IMT, while those associated with periodontal health are not. In INVEST period 2, we demonstrated that progression of atherosclerosis parallels the longitudinal course of the periodontal infections, after adjustment for cardiovascular risk factors, thus establishing a plausible time sequence of periodontal infection and vascular disease, an essential component in attributing causality. Having confirmed our hypothesis that periodontal disease correlates with atherosclerosis both cross-sectionally and prospectively, we now aim to answer the next two critical questions related to causal inference: Does the relationship of periodontal disease with atherosclerosis translate into clinical CVD events? And is periodontal intervention capable of impacting atherosclerotic progression in a subset of our cohort? We propose a novel design within our ongoing cohort to answer both questions. Thus, our first aim is to continue followup of our cohort of 1,014 alive subjects to provide the first evidence of direct association between periodontal microbiology and incident clinical vascular events, beyond subclinical atherosclerosis. Our second aim is to concurrently assess among a random sample of cohort participants(<75yrs), whether achieving and maintaining periodontal health modifies the trajectory of IMT, compared to the regularly followed cohort participants of the same age. This proposal represents the logical culmination of 10 years of research, where we are on the threshold of definitive answers in a population where: i) we have preliminary data supporting the notion that periodontal bacterial colonization levels can predict incident CVD events; ii) parallel progression of both periodontal disease and carotid atherosclerosis have been quantified; and iii) our ability to follow and retain participants has been demonstrated. Our collaborative team of investigators in the fields of periodontology, neurology, CVD epidemiology and biostatistics has been maintained. We thus propose to continue to build on the unique opportunity of our joint efforts in an on-going randomly selected cohort in northern Manhattan where Blacks, Whites and Hispanics have already been thoroughly medically examined and evaluated at baseline and followup for known risk factors for atherosclerosis and stroke, clinical and microbiological periodontal status and host immunologic response. Our study represents a cost-effective, methodologically robust approach, systematically laying the missing blocks for causal inference.